CD8 T cells are critical in controlling infection by intracellular pathogens including viruses and intracellular bacteria. CD8 T cell-mediated immune responses consist of several distinct stages, including activation of antigen-specific nave CD8 T cells, clonal expansion of effector CD8 T cells, and formation of memory CD8 T cells. Among effector CD8 T cells, the KLRG1+IL-7R- cells are considered to be terminally differentiated cytolytic effectors, and KLRG1loIL-7R+ cells have increased potential to give rise to long-lasting memory CD8 T cells and deemed to be memory precursors. Among memory CD8 T cells, CD62L+ central memory T cells are more efficient in homestatic self-renewal and secondary proliferation than CD62L- effector memory T cells. The T cell factor 1 (TCF1) transcription factor is known to mediate the canonical Wnt signaling and play important roles in T cell development. In recent years, studies by us and others discovered its emerging roles in regulating mature CD8 T cell responses. Specifically, activation of the Wnt signaling pathway in CD8 T cells was sufficient to expand the memory CD8 T cell pool. Furthermore, among all the transcription factors that have been studied in CD8 T cell responses to date, TCF1 deficiency most profoundly impaired central memory T cell maturation, memory T cell persistence and secondary expansion. Our preliminary studies further revealed that albeit TCF1 was significantly downregulated in KLRG1+IL-7R- effector T cells, substantial expression of TCF1 was retained in KLRG1loIL-7R+ memory precursors and CD62L+ central memory cells. In addition, loss of TCF1 greatly diminished the frequency of memory precursors at the effector phase. Based on these findings, we hypothesize that TCF1 controls unique transcriptional programs during CD8 T cell responses and retention of TCF1 and its downstream genes in CD8 effectors favors differentiation of memory precursors and formation of self-renewing central memory T cells. We propose to test this hypothesis through the following specific aims: Specific Aim 1. To elucidate the TCF1-regulated gene regulatory circuits throughout the CD8 T cell responses. Specific Aim 2. To identify TCF1 downstream genes that promote generation of memory precursors and central memory T cells. Through these proposed studies, what we will achieve is to elucidate the molecular wiring of TCF1-controlled gene regulatory program and determine its functional importance in promoting generation of robust and long- lasting memory CD8 T cells. These systematic approaches may lead to discovery of key determinants directing CD8 effectors to a memory fate. This project will have a major impact on devising strategies to utilize Wnt- derived signals or their molecular targets to improve vaccine/adjuvant design, aiming for enhanced T cell immunity against infectious agents and malignant cells.